Chroman derivatives and uses thereof

ABSTRACT

Compounds of the formula I:  
                 
or pharmaceutically acceptable salts thereof, 
 
wherein m, p, q, Ar, R 1 , R 2 , R 3  and R 4  are as defined herein. Also provided are methods for preparing, compositions comprising, and methods for using compounds of formula I.

CROSS-REFERENCE

This application claims the benefit of priority of U.S. ProvisionalPatent Application Ser. No. 60/637,792 filed Dec. 21, 2004, thedisclosure of which is incorporated herein by reference in its entirety.

FIELD OF THE INVENTION

This invention relates to substituted chroman compounds, and associatedcompositions, methods for use as therapeutic agents, and methods ofpreparation thereof.

BACKGROUND OF THE INVENTION

The actions of 5-hydroxytryptamine (5-HT) as a major modulatoryneurotransmitter in the brain are mediated through a number of receptorfamilies termed 5-HT1, 5-HT2, 5-HT3, 5-HT4, 5-HT5, 5-HT6, and 5-HT7.Based on a high level of 5-HT6 receptor mRNA in the brain, it has beenstated that the 5-HT6 receptor may play a role in the pathology andtreatment of central nerve system disorders. In particular,5-HT2-selective and 5-HT6 selective ligands have been identified aspotentially useful in the treatment of certain CNS disorders such asParkinson's disease, Huntington's disease, anxiety, depression, manicdepression, psychoses, epilepsy, obsessive compulsive disorders, mooddisorders, migraine, Alzheimer's disease (enhancement of cognitivememory), sleep disorders, feeding disorders such as anorexia, bulimiaand obesity, panic attacks, akathisia, attention deficit hyperactivitydisorder (ADHD), attention deficit disorder (ADD), withdrawal from drugabuse such as cocaine, ethanol, nicotine and benzodiazepines,schizophrenia, and also disorders associated with spinal trauma and/orhead injury such as hydrocephalus. Such compounds are also expected tobe of use in the treatment of certain gastrointestinal (GI) disorderssuch as functional bowel disorder. See for example, B. L. Roth et al.,J. Pharmacol. Exp. Ther., 1994, 268, pages 1403-14120, D. R. Sibley etal., Mol. Pharmacol., 1993, 43, 320-327, A. J. Sleight et al.,Neurotransmission, 1995, 11, 1-5, and A. J. Sleight et al., Serotonin IDResearch Alert, 1997, 2(3), 115-8.

While some 5-HT6 and 5-HT2A modulators have been disclosed, therecontinues to be a need for compounds that are useful for modulating the5-HT6 receptor, the 5-HT2A receptor, or both.

SUMMARY

The invention provides compounds of the formula I:

or a pharmaceutically acceptable salt thereof,wherein:

m is from 0 to 3;

p is from 1 to 3;

q is 0, 1 or 2;

Ar is optionally substituted aryl or optionally substituted heteroaryl;

each R¹ is independently halo, alkyl, haloalkyl, heteroalkyl, cyano,—S(O)_(t)—R^(a), —C(═O)—NR^(b)R^(c), —SO₂—NR^(b)R^(c),—N(R^(d))—C(═O)—R^(e), —C(═O)N(R^(d))—, or —C(═O)—R^(e), where t is from0 to 2, R^(a), R^(b), R^(c), R^(d) and R^(e) each independently ishydrogen or alkyl, and R^(f) is hydrogen, alkyl, alkoxy or hydroxy;

R² is

X is —O— or —NR⁹—;

n is 2 or 3;

R³, R⁴, R⁵ and R⁶ each independently is hydrogen or alkyl;

R⁷ and R⁸ each independently is hydrogen or alkyl, or R⁷ and R⁸ togetherwith the nitrogen to which they are attached may form afour-to-six-membered ring that optionally includes an additionalheteroatom selected from O, N and S, or one of R⁷ and R⁸ and one of R⁵and R⁶ together with the atoms to which they are attached may form afour-to-six-membered ring that optionally includes an additionalheteroatom selected from O, N and S; and

R⁹ is hydrogen or alkyl, or when R⁷ is hydrogen or methyl, R⁹ togetherwith R⁸ and the atoms to which they are attached may form a six-memberedring.

The invention also provides methods for preparing, methods of using, andpharmaceutical compositions comprising the aforementioned compounds. Onesuch method is for producing a compound of formula e;

wherein m, p, q, Ar, X, R¹, R², R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are as definedherein, the method comprising:

reacting a compound of formula c:

with an alkylating agent of formula d

to the compound of formula e.

DETAILED DESCRIPTION OF THE INVENTION

The invention provides substituted quinolinone compounds, associatedcompositions, methods for use as therapeutic agents, and methods ofpreparation thereof. In specific embodiments the invention providespiperazinyl-substituted quinolinone compounds and associatedpharmaceutical compositions, and methods for using the same in thetreatment of central nervous system (CNS) diseases and gastrointestinaltract disorders.

All publications cited in this disclosure are incorporated herein byreference in their entirety.

Definitions

Unless otherwise stated, the following terms used in this Application,including the specification and claims, have the definitions givenbelow. It must be noted that, as used in the specification and theappended claims, the singular forms “a”, “an,” and “the” include pluralreferents unless the context clearly dictates otherwise.

“Agonist” refers to a compound that enhances the activity of anothercompound or receptor site.

“Alkyl” means the monovalent linear or branched saturated hydrocarbonmoiety, consisting solely of carbon and hydrogen atoms, having from oneto twelve carbon atoms. “Lower alkyl” refers to an alkyl group of one tosix carbon atoms (i.e., “C₁-C₆alkyl”). Examples of alkyl groups include,but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl,sec-butyl, tert-butyl, pentyl, n-hexyl, octyl, dodecyl, and the like.

“Alkylene” means a linear saturated divalent hydrocarbon radical of oneto six carbon atoms or a branched saturated divalent hydrocarbon radicalof three to six carbon atoms, e.g., methylene, ethylene,2,2-dimethylethylene, propylene, 2-methylpropylene, butylene, pentylene,and the like.

“Alkenylene” means a linear unsaturated divalent hydrocarbon radical oftwo to six carbon atoms or a branched saturated divalent hydrocarbonradical of three to six carbon atoms, e.g., ethenylene (—CH═CH—),2,2-dimethylethenylene, propenylene, 2-methylpropenylene, butenylene,pentenylene, and the like.

“Alkoxy” means a group —OR, wherein R is alkyl as defined herein.Examples of alkoxy moieties include, but are not limited to, methoxy,ethoxy, isopropoxy, and the like.

each R independently is hydrogen or alkyl as defined herein.

“Aminoalkyl” means a group —R—R′ wherein R′ is amino and R is alkyleneas defined herein. “Aminoalkyl” includes aminomethyl, aminoethyl,1-aminopropyl, 2-aminopropyl, and the like. The amino moiety of“aminoalkyl” may be substituted once or twice with alkyl to provide“alkylaminoalkyl” and “dialkylaminoalkyl” respectively.“Alkylaminoalkyl” includes methylaminomethyl, methylaminoethyl,methylaminopropyl, ethylaminoethyl and the like. “Dialkylaminoalkyl”includes dimethylaminomethyl, dimethylaminoethyl, dimethylaminopropyl,N-methyl-N-ethylaminoethyl, and the like.

“Antagonist” refers to a compound that diminishes or prevents the actionof another compound or receptor site.

“Aryl” means a monovalent cyclic aromatic hydrocarbon moiety consistingof a mono-, bi- or tricyclic aromatic ring. The aryl group can beoptionally substituted as defined herein. Examples of aryl moietiesinclude, but are not limited to, phenyl, naphthyl, naphthalenyl,phenanthryl, fluorenyl, indenyl, pentalenyl, azulenyl, oxydiphenyl,biphenyl, methylenediphenyl, aminodiphenyl, diphenylsulfidyl,diphenylsulfonyl, diphenylisopropylidenyl, benzodioxanyl, benzofuranyl,benzodioxylyl, benzopyranyl, benzoxazinyl, benzoxazinonyl,benzopiperadinyl, benzopiperazinyl, benzopyrrolidinyl, benzomorpholinyl,methylenedioxyphenyl, ethylenedioxyphenyl, and the like, includingpartially hydrogenated derivatives thereof.

“Arylene” means a divalent aryl radical wherein aryl is as definedherein. “Arylene” includes, for example, ortho-, meta- andpara-phenylene (1,2-phenylene, 1,3-phenylene and 1,4-phenylenerespectively), which may be optionally substituted as defined herein.

“Arylalkyl” and “Aralkyl”, which may be used interchangeably, mean aradical —R—R′where R is an alkylene group and R′ is an aryl group asdefined herein; e.g., benzyl, phenylethyl,3-(3-chlorophenyl)-2-methylpentyl, and the like are examples ofarylalkyl.

“Cycloalkyl” means a saturated carbocyclic moiety consisting of mono- orbicyclic rings. Cycloalkyl can optionally be substituted with one ormore substituents, wherein each substituent is independently hydroxy,alkyl, alkoxy, halo, haloalkyl, amino, monoalkylamino, or dialkylamino,unless otherwise specifically indicated. Examples of cycloalkyl moietiesinclude, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, and the like, including partially unsaturatedderivatives thereof such as cyclohexenyl, cyclopentenyl, and the like.

“Cycloalkylalkyl” means a moiety of the formula —R—R′, where R isalkylene and R′ is cycloalkyl as defined herein.

“Heteroalkyl” means an alkyl radical as defined herein wherein one, twoor three hydrogen atoms have been replaced with a substituentindependently selected from the group consisting of —OR^(a),—NR^(b)R^(c), and —S(O)_(n)R^(d) (where n is an integer from 0 to 2),with the understanding that the point of attachment of the heteroalkylradical is through a carbon atom, wherein R^(a) is hydrogen, acyl,alkyl, cycloalkyl, or cycloalkylalkyl; R^(b) and R^(c) are independentlyof each other hydrogen, acyl, alkyl, cycloalkyl, or cycloalkylalkyl; andwhen n is 0, R^(d) is hydrogen, alkyl, cycloalkyl, or cycloalkylalkyl,and when n is 1 or 2, R^(d) is alkyl, cycloalkyl, cycloalkylalkyl,amino, acylamino, monoalkylamino, or dialkylamino. Representativeexamples include, but are not limited to, methoxy, ethoxy,2-hydroxyethyl, 3-hydroxypropyl, 2-methoxyethyl, 3-methoxypropyl,2-hydroxy-1-hydroxymethylethyl, 2,3-dihydroxypropyl,1-hydroxymethylethyl, 3-hydroxybutyl, 2,3-dihydroxybutyl,2-hydroxy-1-methylpropyl, 2-aminoethyl, 3-aminopropyl,2-methylsulfonylethyl, aminosulfonylmethyl, aminosulfonylethyl,aminosulfonylpropyl, methylaminosulfonylmethyl,methylaminosulfonylethyl, methylaminosulfonylpropyl, and the like.

“Heteroaryl” means a monocyclic or bicyclic monovalent radical of 5 to12 ring atoms having at least one aromatic ring containing one, two, orthree ring heteroatoms selected from N, O, or S, the remaining ringatoms being C, with the understanding that the attachment point of theheteroaryl radical will be on an aromatic ring. The heteroaryl ring maybe optionally substituted as defined herein. Examples of heteroarylmoieties include, but are not limited to, imidazolyl, oxazolyl,isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl,pyrazinyl, thienyl, benzothienyl, thiophenyl, furanyl, pyranyl, pyridyl,pyridinyl, pyridazyl, pyrrolyl, pyrazolyl, pyrimidyl, quinolinyl,isoquinolinyl, benzofuryl, benzothiophenyl, benzothiopyranyl,benzimidazolyl, benzooxazolyl, benzooxadiazolyl, benzothiazolyl,benzothiadiazolyl, benzopyranyl, indolyl, isoindolyl, triazolyl,triazinyl, quinoxalinyl, purinyl, quinazolinyl, quinolizinyl,naphthyridinyl, pteridinyl, carbazolyl, azepinyl, diazepinyl, acridinyland the like, including partially hydrogenated derivatives thereof. Theaforementioned heteroaryl moieties may be partially saturated. Thus,“heteroaryl” includes “imidazolinyl”, tetrahydropyrimidinyl” and thelike.

“Heteroarylene” means a divalent heteroaryl radical wherein heteroarylis as defined herein. “Heteroarylene” may be optionally substituted asdefined herein. “Heteroarylene” includes, for example, indolylene,pyrimidinylene, and the like.

The terms “halo” and “halogen”, which may be used interchangeably, referto a substituent fluoro, chloro, bromo, or iodo.

“Haloalkyl” means alkyl as defined herein in which one or more hydrogenhas been replaced with same or different halogen. Exemplary haloalkylsinclude —CH₂Cl, —CH₂CF₃, —CH₂CCl₃, perfluoroalkyl (e.g., —CF₃), and thelike.

“Heterocycloamino” means a saturated ring wherein at least one ring atomis N, NH or N-alkyl and the remaining ring atoms form an alkylene group.

“Heterocyclyl” means a monovalent saturated moiety, consisting of one tothree rings, incorporating one, two, or three or four heteroatoms(chosen from nitrogen, oxygen or sulfur). The heterocyclyl ring may beoptionally substituted as defined herein. Examples of heterocyclylmoieties include, but are not limited to, piperidinyl, piperazinyl,homopiperazinyl, azepinyl, pyrrolidinyl, pyrazolidinyl, imidazolinyl,imidazolidinyl, pyridinyl, pyridazinyl, oxazolidinyl, isoxazolidinyl,morpholinyl, thiazolidinyl, isothiazolidinyl, quinuclidinyl, quinolinyl,isoquinolinyl, benzimidazolyl, thiadiazolylidinyl, benzothiazolidinyl,benzoazolylidinyl, dihydrofuryl, tetrahydrofuryl, dihydropyranyl,tetrahydropyranyl, thiamorpholinyl, thiamorpholinylsulfoxide,thiamorpholinylsulfone, dihydroquinolinyl, dihydrisoquinolinyl,tetrahydroquinolinyl, tetrahydrisoquinolinyl, and the like, includingpartially unsaturated derivatives thereof.

“Optionally substituted”, when used in association with “aryl”, phenyl”,“heteroaryl”, cycloalkyl or “heterocyclyl”, means an aryl, phenyl,heteroaryl, or heterocyclyl which is optionally substitutedindependently with one to four substituents, preferably one or twosubstituents selected from alkyl, cycloalkyl, cycloalkylalkyl,heteroalkyl, hydroxyalkyl, halo, nitro, cyano, hydroxy, alkoxy, amino,acylamino, mono-alkylamino, di-alkylamino, haloalkyl, haloalkoxy,heteroalkyl, —COR (where R is hydrogen, alkyl, phenyl or phenylalkyl),—(CR′R″)_(n)—COOR (where n is an integer from 0 to 5, R′ and R″ areindependently hydrogen or alkyl, and R is hydrogen, alkyl, cycloalkyl,cycloalkylalkyl, phenyl or phenylalkyl), or —(CR′R″)_(n)—CONR^(a)R^(b)(where n is an integer from 0 to 5, R′ and R″ are independently hydrogenor alkyl, and R^(a) and R^(b) are, independently of each other,hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, phenyl or phenylalkyl.

“Leaving group” means the group with the meaning conventionallyassociated with it in synthetic organic chemistry, i.e., an atom orgroup displaceable under substitution reaction conditions. Examples ofleaving groups include, but are not limited to, halogen, alkane- orarylenesulfonyloxy, such as methanesulfonyloxy, ethanesulfonyloxy,thiomethyl, benzenesulfonyloxy, tosyloxy, and thienyloxy,dihalophosphinoyloxy, optionally substituted benzyloxy, isopropyloxy,acyloxy, and the like.

“Modulator” means a molecule that interacts with a target. Theinteractions include, but are not limited to, agonist, antagonist, andthe like, as defined herein.

“Optional” or “optionally” means that the subsequently described eventor circumstance may but need not occur, and that the descriptionincludes instances where the event or circumstance occurs and instancesin which it does not.

“Disease state” means any disease, condition, symptom, or indication.

“Inert organic solvent” or “inert solvent” means the solvent is inertunder the conditions of the reaction being described in conjunctiontherewith, including for example, benzene, toluene, acetonitrile,tetrahydrofuran, N,N-dimethylformamide, chloroform, methylene chlorideor dichloromethane, dichloroethane, diethyl ether, ethyl acetate,acetone, methyl ethyl ketone, methanol, ethanol, propanol, isopropanol,tert-butanol, dioxane, pyridine, and the like. Unless specified to thecontrary, the solvents used in the reactions of the present inventionare inert solvents.

“Pharmaceutically acceptable” means that which is useful in preparing apharmaceutical composition that is generally safe, non-toxic, andneither biologically nor otherwise undesirable and includes that whichis acceptable for veterinary as well as human pharmaceutical use.

“Pharmaceutically acceptable salts” of a compound means salts that arepharmaceutically acceptable, as defined herein, and that possess thedesired pharmacological activity of the parent compound. Such saltsinclude:

-   -   acid addition salts formed with inorganic acids such as        hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,        phosphoric acid, and the like; or formed with organic acids such        as acetic acid, benzenesulfonic acid, benzoic, camphorsulfonic        acid, citric acid, ethanesulfonic acid, fumaric acid,        glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid,        hydroxynaphtoic acid, 2-hydroxyethanesulfonic acid, lactic acid,        maleic acid, malic acid, malonic acid, mandelic acid,        methanesulfonic acid, muconic acid, 2-naphthalenesulfonic acid,        propionic acid, salicylic acid, succinic acid, tartaric acid,        p-toluenesulfonic acid, trimethylacetic acid, and the like; or    -   salts formed when an acidic proton present in the parent        compound either is replaced by a metal ion, e.g., an alkali        metal ion, an alkaline earth ion, or an aluminum ion; or        coordinates with an organic or inorganic base. Acceptable        organic bases include diethanolamine, ethanolamine,        N-methylglucamine, triethanolamine, tromethamine, and the like.        Acceptable inorganic bases include aluminum hydroxide, calcium        hydroxide, potassium hydroxide, sodium carbonate and sodium        hydroxide.

The preferred pharmaceutically acceptable salts are the salts formedfrom acetic acid, hydrochloric acid, sulphuric acid, methanesulfonicacid, maleic acid, phosphoric acid, tartaric acid, citric acid, sodium,potassium, calcium, zinc, and magnesium.

It should be understood that all references to pharmaceuticallyacceptable salts include solvent addition forms (solvates) or crystalforms (polymorphs) as defined herein, of the same acid addition salt.

The terms “pro-drug” and “prodrug”, which may be used interchangeablyherein, refer to any compound which releases an active parent drugaccording to formula I in vivo when such prodrug is administered to amammalian subject. Prodrugs of a compound of formula I are prepared bymodifying one or more functional group(s) present in the compound offormula I in such a way that the modification(s) may be cleaved in vivoto release the parent compound. Prodrugs include compounds of formula Iwherein a hydroxy, amino, or sulfhydryl group in a compound of Formula Iis bonded to any group that may be cleaved in vivo to regenerate thefree hydroxyl, amino, or sulfhydryl group, respectively. Examples ofprodrugs include, but are not limited to, esters (e.g., acetate,formate, and benzoate derivatives), carbamates (e.g.,N,N-dimethylaminocarbonyl) of hydroxy functional groups in compounds offormula I, N-acyl derivatives (e.g. N-acetyl) N-Mannich bases, Schiffbases and enaminones of amino functional groups, oximes, acetals, ketalsand enol esters of ketone and aldehyde functional groups in compounds ofFormula I, and the like, see Bundegaard, H. “Design of Prodrugs” p1-92,Elesevier, New York-Oxford (1985), and the like.

“Protective group” or “protecting group” means the group whichselectively blocks one reactive site in a multifunctional compound suchthat a chemical reaction can be carried out selectively at anotherunprotected reactive site in the meaning conventionally associated withit in synthetic chemistry. Certain processes of this invention rely uponthe protective groups to block reactive nitrogen and/or oxygen atomspresent in the reactants. For example, the terms “amino-protectinggroup” and “nitrogen protecting group” are used interchangeably hereinand refer to those organic groups intended to protect the nitrogen atomagainst undesirable reactions during synthetic procedures. Exemplarynitrogen protecting groups include, but are not limited to,trifluoroacetyl, acetamido, benzyl (Bn), benzyloxycarbonyl(carbobenzyloxy, CBZ), p-methoxybenzyloxycarbonyl,p-nitrobenzyloxycarbonyl, tert-butoxycarbonyl (BOC), and the like. Thoseskilled in the art know how to choose a group for the ease of removaland for the ability to withstand the following reactions.

“Solvates” means solvent addition forms that contain eitherstoichiometric or non stoichiometric amounts of solvent. Some compoundshave a tendency to trap a fixed molar ratio of solvent molecules in thecrystalline solid state, thus forming a solvate. If the solvent is waterthe solvate formed is a hydrate, when the solvent is alcohol, thesolvate formed is an alcoholate. Hydrates are formed by the combinationof one or more molecules of water with one of the substances in whichthe water retains its molecular state as H₂O, such combination beingable to form one or more hydrate.

“Subject” means mammals and non-mammals. Mammals means any member of themammalia class including, but not limited to, humans; non-human primatessuch as chimpanzees and other apes and monkey species; farm animals suchas cattle, horses, sheep, goats, and swine; domestic animals such asrabbits, dogs, and cats; laboratory animals including rodents, such asrats, mice, and guinea pigs; and the like. Examples of non-mammalsinclude, but are not limited to, birds, and the like. The term “subject”does not denote a particular age or sex.

“Therapeutically effective amount” means an amount of a compound that,when administered to a subject for treating a disease state, issufficient to effect such treatment for the disease state. The“therapeutically effective amount” will vary depending on the compound,disease state being treated, the severity or the disease treated, theage and relative health of the subject, the route and form ofadministration, the judgement of the attending medical or veterinarypractitioner, and other factors.

The terms “those defined above” and “those defined herein” whenreferring to a variable incorporates by reference the broad definitionof the variable as well as preferred, more preferred and most preferreddefinitions, if any.

“Treating” or “treatment” of a disease state includes:

-   -   (i) preventing the disease state, i.e. causing the clinical        symptoms of the disease state not to develop in a subject that        may be exposed to or predisposed to the disease state, but does        not yet experience or display symptoms of the disease state.    -   (ii) inhibiting the disease state, i.e., arresting the        development of the disease state or its clinical symptoms, or    -   (iii) relieving the disease state, i.e., causing temporary or        permanent regression of the disease state or its clinical        symptoms.

The terms “treating”, “contacting” and “reacting” when referring to achemical reaction means adding or mixing two or more reagents underappropriate conditions to produce the indicated and/or the desiredproduct. It should be appreciated that the reaction which produces theindicated and/or the desired product may not necessarily result directlyfrom the combination of two reagents which were initially added, i.e.,there may be one or more intermediates which are produced in the mixturewhich ultimately leads to the formation of the indicated and/or thedesired product.

Nomenclature

In general, the nomenclature used in this Application is based onAUTONOM™ v.4.0, a Beilstein Institute computerized system for thegeneration of IUPAC systematic nomenclature.

Chemical structures shown herein were prepared using ISIS® version 2.2.Any open valency appearing on a carbon, oxygen or nitrogen atom in thestructures herein indicates the presence of a hydrogen.

Compounds of the Invention

The invention provides compounds of the formula I:It should be understood that the scope of this invention encompasses notonly the various isomers which may exist but also the various mixture ofisomers which may be formed. Furthermore, the scope of the presentinvention also encompasses solvates and salts of compounds of formula I:

or a pharmaceutically acceptable salt thereof,wherein:

m is from 0 to 3;

p is from 1 to 3;

q is 0, 1 or 2;

Ar is optionally substituted aryl or optionally substituted heteroaryl;

each R¹ is independently halo, alkyl, haloalkyl, heteroalkyl, cyano,—S(O)_(t)—R^(a), —C(═O)—NR^(b)R^(c), —SO₂—NR^(b)R^(c),—N(R^(d))—C(═O)—R^(e), —C(═O)N(R^(d))—, or —C(═O)—R^(e), where t is from0 to 2, R^(a), R^(b), R^(c), R^(d) and R^(e) each independently ishydrogen or alkyl, and R^(f) is hydrogen, alkyl, alkoxy or hydroxy;

R² is

X is —O— or —NR⁹—;

-   n is 2 or 3;

R³, R⁴, R⁵ and R⁶ each independently is hydrogen or alkyl;

R⁷ and R⁸ each independently is hydrogen or alkyl, or R⁷ and R⁸ togetherwith the nitrogen to which they are attached may form afour-to-six-membered ring that optionally includes an additionalheteroatom selected from O, N and S, or one of R⁷ and R⁸ and one of R⁵and R⁶ together with the atoms to which they are attached may form afour-to-six-membered ring that optionally includes an additionalheteroatom selected from O, N and S; and

R⁹ is hydrogen or alkyl, or when R⁷ is hydrogen or methyl, R⁹ togetherwith R⁸ and the atoms to which they are attached may form a six-memberedring.

In certain embodiments of formula I, p is 2. In many such embodiments qis 2.

In certain embodiments of formula I, Ar is optionally substitutedphenyl.

Preferably, m is 0 or 1 in embodiments of formula I.

In many embodiments of formula I, X is —NR⁹—.

In certain embodiments, R³ and R⁴ may both be hydrogen. In other suchembodiments, both R³ and R⁴ may be alkyl, preferably methyl.

In certain embodiments of formula I, n is 2.

In certain embodiments of formula I, n is 3

In certain embodiments, of formula I, R⁵ and R⁶ may both be hydrogen. Inother embodiments R⁷ and R⁸ is hydrogen and the other is alkyl,preferably methyl. In still other embodiments, R⁷ and R⁸ are both alkyl,preferably methyl.

In certain embodiments of formula I, R⁷ and R⁸ together with thenitrogen to which they are attached may form six-membered ring.

In certain embodiments of formula I, R⁹ is hydrogen.

In certain embodiments of formula I, R⁷ is hydrogen or methyl, and R⁸and R⁹ together with the atoms to which they are attached form asix-membered ring.

In many embodiments of the invention the subject compounds are of theformula II:

wherein m, q, Ar, R¹, R², R³ and R⁴ are as defined herein.

In certain embodiments of formula II, q is 2.

In certain embodiments of formula II, Ar is optionally substitutedphenyl.

Preferably, m is 0 or 1 in embodiments of formula I.

In many embodiments of formula II, X is —NR⁹—.

In certain embodiments of formula II, R³ and R⁴ may both be hydrogen. Inother such embodiments, both R³ and R⁴ may be alkyl, preferably methyl.

In certain embodiments of formula II, n is 2.

In certain embodiments of formula II, n is 3

In certain embodiments, of formula II, R⁵ and R⁶ may both be hydrogen.In other embodiments R⁷ and R⁸ is hydrogen and the other is alkyl,preferably methyl. In still other embodiments, R⁷ and R⁸ are both alkyl,preferably methyl.

In certain embodiments of formula I, R⁷ and R⁸ together with thenitrogen to which they are attached may form six-membered ring.

In certain embodiments of formula II, R⁹ is hydrogen.

In certain embodiments of formula II, R⁷ is hydrogen or methyl, and R⁸and R⁹ together with the atoms to which they are attached form asix-membered ring.

In certain embodiments of the invention the subject compounds are morespecifically of the formula III:

wherein:

s is from 0 to 4;

each R¹⁰ is independently halo, alkyl, haloalkyl, heteroalkyl, cyano,—S(O)_(t)—R^(a), —C(═O)—NR^(b)R^(c), —SO₂—NR^(b)R^(c),—N(R^(d))—C(═O)—R^(e), —C(═O)N(R^(d))—, or —C(═O)—R^(e), where t is from0 to 2, R^(a), R^(b), R^(c), R^(d) and R^(e) each independently ishydrogen or alkyl, and R^(f) is hydrogen, alkyl, alkoxy or hydroxy; and

X, R⁷ and R⁸ are as defined herein.

Preferably, s is from 0 to 2 and R¹⁰ is halo, alkyl, alkoxy orhaloalkyl. More preferably, s is 0 or 1 and R¹⁰ is fluoro or chloro.

In many embodiments of formula III, X is —NR⁹—.

In certain embodiments of formula III, n is 2.

In certain embodiments of formula III, n is 3

In certain embodiments, of formula III, R⁵ and R⁶ may both be hydrogen.In other embodiments R⁷ and R⁸ is hydrogen and the other is alkyl,preferably methyl. In still other embodiments, R⁷ and R⁸ are both alkyl,preferably methyl.

In certain embodiments of formula III, R⁷ and R⁸ together with thenitrogen to which they are attached may form six-membered ring.

In certain embodiments of formula III, R⁹ is hydrogen.

In certain embodiments of formula III, R⁷ is hydrogen or methyl, and R⁸and R⁹ together with the atoms to which they are attached form asix-membered ring.

In certain embodiments of the invention the subject compounds are morespecifically of the formula IV:

wherein:

s is from 0 to 4;

each R¹⁰ is independently halo, alkyl, haloalkyl, heteroalkyl, cyano,—S(O)_(t)—R^(a), —C(═O)—NR^(b)R^(c), —SO₂—NR^(b)R^(c),—N(R^(d))—C(═O)—R^(e), —C(═O)N(R^(d))—, or —C(═O)—R^(e), where t is from0 to 2, R^(a), R^(b), R^(c), R^(d) and R^(e) each independently ishydrogen or alkyl, and R^(f) is hydrogen, alkyl, alkoxy or hydroxy; and

-   -   R⁷ is hydrogen or methyl.

Preferably, s is from 0 to 2 and R¹⁰ is halo, alkyl, alkoxy orhaloalkyl. More preferably, s is 0 or 1 and R¹⁰ is fluoro or chloro.

Where any of R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R^(a), R^(b),R^(c), R^(d), and R^(e) herein are alkyl or contain an alkyl moiety,such alkyl is preferably lower alkyl, i.e. C₁-C₆alkyl, and morepreferably C₁-C₄alkyl.

Representative compounds in accordance with the invention are shown inTable 1 below. TABLE 1 MP, ° C. or # Structure Name (M+H) 1

1-(7-Benzenesulfonyl-chroman-4-yl)-piperazine 243.0-249.0° C. (HCl Salt)2

(7-Benzenesulfonyl-chroman-4-yl)-(2-piperidin-1-yl- ethyl)-amine154.1-153.2° C. (HCl Salt) 3

N′-(7-Benzenesulfonyl-chroman-4-yl)-N,N- dimethyl-ethane-1,2-diamine 3614

N′-(7-Benzenesulfonyl-chroman-4-yl)-N,N- dimethyl-propane-1,3-diamine376 5

1-[7-(3-Fluoro-benzenesulfonyl)-2,2-dimethyl- chroman-4-yl]-piperazine406 6

1-(7-Benzenesulfonyl-2,2-dimethyl-chroman-4-yl)- piperazine 388 7

1-[7-(3-Fluoro-benzenesulfonyl)-chroman-4-yl]-4- methyl-piperazine 391 8

N′-[7-(3-Fluoro-benzenesulfonyl)-chroman-4-yl]-N,N-dimethyl-propane-1,3-diamine 393 9

1-[7-(4-Fluoro-benzenesulfonyl)-chroman-4-yl]- piperazine 377 10

N′-[7-(3-Fluoro-benzenesulfonyl)-chroman-4-yl]-N,N-dimethyl-ethane-1,2-diamine 379 11

1-[7-(3-Fluoro-benzenesulfonyl)-chroman-4-yl]- piperazine 377 12

[7-(3-Fluoro-benzenesulfonyl)-chroman-4-yl]-(1-methyl-piperidin-4-yl)-amine 405

Another aspect of the invention provides a composition comprising atherapeutically effective amount of at least one compound of formula (I)and a pharmaceutically acceptable carrier.

Yet another aspect of the invention provides a method for treating acentral nervous system (CNS) disease state in a subject comprisingadministering to the subject a therapeutically effective amount of acompound of formula I. The disease state may comprise, for example,psychoses, schizophrenia, manic depressions, neurological disorders,memory disorders, attention deficit disorder, Parkinson's disease,amyotrophic lateral sclerosis, Alzheimer's disease or Huntington'sdisease.

Still another aspect of the present invention provides a method fortreating a disorder of the gastrointestinal tract in a subjectcomprising administering to the subject a therapeutically effectiveamount of a compound of formula (I).

Another aspect of the present invention provides a method for producinga compound of formula (I).

Synthesis

Compounds of the present invention can be made by a variety of methodsdepicted in the illustrative synthetic reaction schemes shown anddescribed below.

The starting materials and reagents used in preparing these compoundsgenerally are either available from commercial suppliers, such asAldrich Chemical Co., or are prepared by methods known to those skilledin the art following procedures set forth in references such as Fieserand Fieser's Reagents for Organic Synthesis; Wiley & Sons: New York,1991, Volumes 1-15; Rodd's Chemistry of Carbon Compounds, ElsevierScience Publishers, 1989, Volumes 1-5 and Supplementals; and OrganicReactions, Wiley & Sons: New York, 2004, Volumes 1-56. The followingsynthetic reaction schemes are merely illustrative of some methods bywhich the compounds of the present invention can be synthesized, andvarious modifications to these synthetic reaction schemes can be madeand will be suggested to one skilled in the art having referred to thedisclosure contained in this Application.

The starting materials and the intermediates of the synthetic reactionschemes can be isolated and purified if desired using conventionaltechniques, including but not limited to, filtration, distillation,crystallization, chromatography, and the like. Such materials can becharacterized using conventional means, including physical constants andspectral data.

Unless specified to the contrary, the reactions described hereinpreferably are conducted under an inert atmosphere at atmosphericpressure at a reaction temperature range of from about −78° C. to about150° C., more preferably from about 0° C. to about 125° C., and mostpreferably and conveniently at about room (or ambient) temperature,e.g., about 20° C.

Scheme A below illustrates one synthetic procedure usable to preparecompounds of the invention, wherein X, Ar, m, p, q, R¹, R³, R⁴, R⁵ andR⁶ are as defined herein. Numerous synthetic routes to indanes andtetralins are known and may be used in preparation of the subjectcompounds, and the procedure of Scheme A is only exemplary. Specificexamples of the procedure of Scheme A are provided in the followingExperimental section.

In step 1 of Scheme A, ketone compound a is reduced to give alcoholcompound b. Ketone compound may comprise, for example, an arylsulfonyldihydrobenzofuranone where q is 2 and p 1, an arylsulfonyl chroman whereq is 2 and p is 2, or like ketone in accordance with the invention.Corresponding, arylsulfanyl (q=0) and arylsulfinyl (q=1) ketonecompounds may be used in this step. Ketone compounds a may be preparedby a variety of techniques known in the art, and specific examples ofpreparing such compounds are provided below in the Experimental sectionof this disclosure. The reduction reaction of step 1 may be achieved bytreatment of ketone compound a with sodium borohydride under mild proticsolvent conditions.

In step 2, alcohol compound b is subject to chlorination to providenitrile chloro compound c. This reaction may be achieved using thionylchloride under non-polar solvent conditions.

An alkylation reaction is carried out in step 3 by reaction of compoundd with chlorine compound c to yield compound e, which is a compound offormula I in accordance with the invention. In compound d X may be —O—or —NR⁹— where R⁹ is as defined above. Where one or both of R⁷ and R⁸are hydrogen, suitable protection and deprotection strategies may beemployed in this step.

Many variations on the procedure of Scheme A are possible and will bereadily apparent to those skilled in the art. In certain embodimentswhere X is 0, steps 2 and 3 may be replaced with an O-alkylationreaction by treatment of compound b with a suitable aminoalkyl halide,or a heteroalkyl halide that may subsequently be modified to introducean amine functionality. In certain instances, ketone a may be treateddirectly with a secondary amine under reducing conditions to directlyprovide compound e.

Specific details for producing compounds of formula I are described inthe Examples section below.

Utility

The compounds of the invention have selective affinity for 5-HTreceptors, including the 5-HT₆ the 5-HT_(2A) receptor, or both, and assuch are expected to be useful in the treatment of certain CNS disorderssuch as Parkinson's disease, Huntington's disease, anxiety, depression,manic depression, psychosis, epilepsy, obsessive compulsive disorders,mood disorders, migraine, Alzheimer's disease (enhancement of cognitivememory), sleep disorders, feeding disorders such as anorexia, bulimia,and obesity, panic attacks, akathisia, attention deficit hyperactivitydisorder (ADHD), attention deficit disorder (ADD), withdrawal from drugabuse such as cocaine, ethanol, nicotine and benzodiazepines,schizophrenia, and also disorders associated with spinal trauma and/orhead injury such as hydrocephalus. Such compounds are also expected tobe of use in the treatment of certain GI (gastrointestinal) disorderssuch functional bowel disorder and irritable bowel syndrome.

Testing

The pharmacology of the compounds of this invention was determined byart recognized procedures. The in vitro techniques for determining theaffinities of test compounds at the 5-HT6 receptor and the 5-HT2Areceptor in radioligand binding, FLIPR and functional assays aredescribed below.

Administration and Pharmaceutical Composition

The present invention includes pharmaceutical compositions comprising atleast one compound of the present invention, or an individual isomer,racemic or non-racemic mixture of isomers or a pharmaceuticallyacceptable salt or solvate thereof, together with at least onepharmaceutically acceptable carrier, and optionally other therapeuticand/or prophylactic ingredients.

In general, the compounds of the present invention will be administeredin a therapeutically effective amount by any of the accepted modes ofadministration for agents that serve similar utilities. Suitable dosageranges are typically 1-500 mg daily, preferably 1-100 mg daily, and mostpreferably 1-30 mg daily, depending upon numerous factors such as theseverity of the disease to be treated, the age and relative health ofthe subject, the potency of the compound used, the route and form ofadministration, the indication towards which the administration isdirected, and the preferences and experience of the medical practitionerinvolved. One of ordinary skill in the art of treating such diseaseswill be able, without undue experimentation and in reliance uponpersonal knowledge and the disclosure of this Application, to ascertaina therapeutically effective amount of the compounds of the presentinvention for a given disease.

In general, compounds of the present invention will be administered aspharmaceutical formulations including those suitable for oral (includingbuccal and sub-lingual), rectal, nasal, topical, pulmonary, vaginal, orparenteral (including intramuscular, intraarterial, intrathecal,subcutaneous and intravenous) administration or in a form suitable foradministration by inhalation or insufflation. The preferred manner ofadministration is generally oral using a convenient daily dosage regimenwhich can be adjusted according to the degree of affliction.

A compound or compounds of the present invention, together with one ormore conventional adjuvants, carriers, or diluents, may be placed intothe form of pharmaceutical compositions and unit dosages. Thepharmaceutical compositions and unit dosage forms may be comprised ofconventional ingredients in conventional proportions, with or withoutadditional active compounds or principles, and the unit dosage forms maycontain any suitable effective amount of the active ingredientcommensurate with the intended daily dosage range to be employed. Thepharmaceutical compositions may be employed as solids, such as tabletsor filled capsules, semisolids, powders, sustained release formulations,or liquids such as solutions, suspensions, emulsions, elixirs, or filledcapsules for oral use; or in the form of suppositories for rectal orvaginal administration; or in the form of sterile injectable solutionsfor parenteral use. Formulations containing about one (1) milligram ofactive ingredient or, more broadly, about 0.01 to about one hundred(100) milligrams, per tablet, are accordingly suitable representativeunit dosage forms.

The compounds of the present invention may be formulated in a widevariety of oral administration dosage forms. The pharmaceuticalcompositions and dosage forms may comprise a compound or compounds ofthe present invention or pharmaceutically acceptable salts thereof asthe active component. The pharmaceutically acceptable carriers may beeither solid or liquid. Solid form preparations include powders,tablets, pills, capsules, cachets, suppositories, and dispersiblegranules. A solid carrier may be one or more substances which may alsoact as diluents, flavouring agents, solubilizers, lubricants, suspendingagents, binders, preservatives, tablet disintegrating agents, or anencapsulating material. In powders, the carrier generally is a finelydivided solid which is a mixture with the finely divided activecomponent. In tablets, the active component generally is mixed with thecarrier having the necessary binding capacity in suitable proportionsand compacted in the shape and size desired. The powders and tabletspreferably contain from about one (1) to about seventy (70) percent ofthe active compound. Suitable carriers include but are not limited tomagnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin,dextrin, starch, gelatine, tragacanth, methylcellulose, sodiumcarboxymethylcellulose, a low melting wax, cocoa butter, and the like.The term “preparation” is intended to include the formulation of theactive compound with encapsulating material as carrier, providing acapsule in which the active component, with or without carriers, issurrounded by a carrier, which is in association with it. Similarly,cachets and lozenges are included. Tablets, powders, capsules, pills,cachets, and lozenges may be as solid forms suitable for oraladministration.

Other forms suitable for oral administration include liquid formpreparations including emulsions, syrups, elixirs, aqueous solutions,aqueous suspensions, or solid form preparations which are intended to beconverted shortly before use to liquid form preparations. Emulsions maybe prepared in solutions, for example, in aqueous propylene glycolsolutions or may contain emulsifying agents, for example, such aslecithin, sorbitan monooleate, or acacia. Aqueous solutions can beprepared by dissolving the active component in water and adding suitablecolorants, flavors, stabilizers, and thickening agents. Aqueoussuspensions can be prepared by dispersing the finely divided activecomponent in water with viscous material, such as natural or syntheticgums, resins, methylcellulose, sodium carboxymethylcellulose, and otherwell known suspending agents. Solid form preparations include solutions,suspensions, and emulsions, and may contain, in addition to the activecomponent, colorants, flavors, stabilizers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents, andthe like.

The compounds of the present invention may be formulated for parenteraladministration (e.g., by injection, for example bolus injection orcontinuous infusion) and may be presented in unit dose form in ampoules,pre-filled syringes, small volume infusion or in multi-dose containerswith an added preservative. The compositions may take such forms assuspensions, solutions, or emulsions in oily or aqueous vehicles, forexample solutions in aqueous polyethylene glycol. Examples of oily ornonaqueous carriers, diluents, solvents or vehicles include propyleneglycol, polyethylene glycol, vegetable oils (e.g., olive oil), andinjectable organic esters (e.g., ethyl oleate), and may containformulatory agents such as preserving, wetting, emulsifying orsuspending, stabilizing and/or dispersing agents. Alternatively, theactive ingredient may be in powder form, obtained by aseptic isolationof sterile solid or by lyophilization from solution for constitutionbefore use with a suitable vehicle, e.g., sterile, pyrogen-free water.

The compounds of the present invention may be formulated for topicaladministration to the epidermis as ointments, creams or lotions, or as atransdermal patch. Ointments and creams may, for example, be formulatedwith an aqueous or oily base with the addition of suitable thickeningand/or gelling agents. Lotions may be formulated with an aqueous or oilybase and will in general also containing one or more emulsifying agents,stabilizing agents, dispersing agents, suspending agents, thickeningagents, or coloring agents. Formulations suitable for topicaladministration in the mouth include lozenges comprising active agents ina flavored base, usually sucrose and acacia or tragacanth; pastillescomprising the active ingredient in an inert base such as gelatine andglycerine or sucrose and acacia; and mouthwashes comprising the activeingredient in a suitable liquid carrier.

The compounds of the present invention may be formulated foradministration as suppositories. A low melting wax, such as a mixture offatty acid glycerides or cocoa butter is first melted and the activecomponent is dispersed homogeneously, for example, by stirring. Themolten homogeneous mixture is then poured into convenient sized molds,allowed to cool, and to solidify.

The compounds of the present invention may be formulated for vaginaladministration. Pessaries, tampons, creams, gels, pastes, foams orsprays containing in addition to the active ingredient such carriers asare known in the art to be appropriate.

The compounds of the present invention may be formulated for nasaladministration. The solutions or suspensions are applied directly to thenasal cavity by conventional means, for example, with a dropper, pipetteor spray. The formulations may be provided in a single or multidoseform. In the latter case of a dropper or pipette, this may be achievedby the patient administering an appropriate, predetermined volume of thesolution or suspension. In the case of a spray, this may be achieved forexample by means of a metering atomizing spray pump.

The compounds of the present invention may be formulated for aerosoladministration, particularly to the respiratory tract and includingintranasal administration. The compound will generally have a smallparticle size for example of the order of five (5) microns or less. Sucha particle size may be obtained by means known in the art, for exampleby micronization. The active ingredient is provided in a pressurizedpack with a suitable propellant such as a chlorofluorocarbon (CFC), forexample, dichlorodifluoromethane, trichlorofluoromethane, ordichlorotetrafluoroethane, or carbon dioxide or other suitable gas. Theaerosol may conveniently also contain a surfactant such as lecithin. Thedose of drug may be controlled by a metered valve. Alternatively theactive ingredients may be provided in a form of a dry powder, forexample a powder mix of the compound in a suitable powder base such aslactose, starch, starch derivatives such as hydroxypropylmethylcellulose and polyvinylpyrrolidine (PVP). The powder carrier will form agel in the nasal cavity. The powder composition may be presented in unitdose form for example in capsules or cartridges of e.g., gelatine orblister packs from which the powder may be administered by means of aninhaler.

When desired, formulations can be prepared with enteric coatings adaptedfor sustained or controlled release administration of the activeingredient. For example, the compounds of the present invention can beformulated in transdermal or subcutaneous drug delivery devices. Thesedelivery systems are advantageous when sustained release of the compoundis necessary and when patient compliance with a treatment regimen iscrucial. Compounds in transdermal delivery systems are frequentlyattached to an skin-adhesive solid support. The compound of interest canalso be combined with a penetration enhancer, e.g., Azone(1-dodecylazacycloheptan-2-one). Sustained release delivery systems areinserted subcutaneously into the subdermal layer by surgery orinjection. The subdermal implants encapsulate the compound in a lipidsoluble membrane, e.g., silicone rubber, or a biodegradable polymer,e.g., polylactic acid.

The pharmaceutical preparations are preferably in unit dosage forms. Insuch form, the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packeted tablets, capsules, and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form.

Other suitable pharmaceutical carriers and their formulations aredescribed in Remington: The Science and Practice of Pharmacy 1995,edited by E. W. Martin, Mack Publishing Company, 19th edition, Easton,Pa. Representative pharmaceutical formulations containing a compound ofthe present invention are described in the Examples below.

EXAMPLES

The following preparations and examples are given to enable thoseskilled in the art to more clearly understand and to practice thepresent invention. They should not be considered as limiting the scopeof the invention, but merely as being illustrative and representativethereof.

Preparation 1 7-Benzenesulfonyl-chroman-4-one

The synthetic procedure described in this Preparation was carried outaccording to the process shown in Scheme D.

Step 1

3-(3-Fluoro-phenoxy)-propionic acid

3-Fluorophenol (8.9 g, 79.5 mmol) and 3-bromopropionic acid (12.24 g,80.0 mmol) were placed in a flask. A solution of NaOH (6.7 g, 167 mmol)in 20 mL water was added slowly to the flask. The reaction mixture washeated to reflux for two hours and then cooled to room temperature andpartitioned between ethyl acetate and water. The organic layer was driedover MgSO₄, and solvent was evaporated under reduced pressure to give4.57 g (25 mmol, 31.4%) of 3-(3-fluoro-phenoxy)-propionic acid. MS: 185(M+H)⁺.

Step 2

7-Fluoro-chroman-4-one

3-(3-Fluoro-phenoxy)-propionic acid (3.37 g, 18.3 mmol), was dissolvedin a mixture of 25 mL trifluoroacetic acid and 9 mL methanesulfonicacid. The reaction mixture was hteated to 90° C. and was stirred at 90°C. for one hour. The reaction mixture was cooled to room temperature andpartitioned between ethyl acetate and water. The organic layer was driedover MgSO₄, and solvent was evaporated under reduced pressure. Theresidue was eluted through silica gel (15% EtOAc in hexanes), andsolvent was removed under reduced pressure to yield 1.24 g (7.5 mmol,41%) of 7-fluoroo-chroman-4-one (MS: 167 (M+H)⁺.

Step 3

7-Phenylsulfanyl-chroman-4-one

A solution of 7-fluoroo-chroman-4-one (1.87 g, 11.27 mmol) and K₂CO₃(9.28 g, 67.12 mmol) was added to 20 mL of dimethylformamide (DMF).Benzenethiol (1.37 mL, 13.52 mmol) was added, and the reaction mixturewas stirred at room temperature for two hours, and then partitionedbetween ethyl acetate and water. The organic layer was dried over MgSO₄,and solvent was evaporated under reduced pressure to yield an oil thatwas eluted through silica gel using hexanes/EtOAc (9:1). Removal ofsolvent under reduced pressure provided 2.21 g (8.62 mmol, 77%) of7-phenylsulfanyl-chroman-4-one. MS: 257 (M+H)⁺.

Step 4

7-Benzenesulfonyl-chroman-4-one

A solution of 7-phenylsulfanyl-chroman-4-one (2.21 g, 8.62 mmol) in 20mL o MeOH and 2 mL water was stirred at room temperature. OXONE™(potassium peroxymonosulfate, 6.35 g, 10.35 mmol) was added, and thereaction mixture was stirred for 3 hours at room temperature. Thereaction mixture was partitioned between ethyl acetate and water. Theorganic layer was dried over MgSO₄, and solvent was evaporated underreduced pressure. The resulting residue was eluted through silica gelwith 35% EtOAc in hexanes. Removal of solvent under reduced pressureafforded 1.56 g (5.41 mmol, 63%) of 7-benzenesulfonyl-chroman-4-one. MS:289 (M+H)⁺.

Using the same procedure but replacing benzenethiol in step 3 with3-fluorobenzenethiol, 7-(3-fluoro-benzenesulfonyl)-chroman-4-one wasprepared.

Preparation 2 7-Benzenesulfonyl-2,2-dimethyl-chroman-4-one

The synthetic procedure described in this Preparation was carried outaccording to the process shown in Scheme E.

Step 1

7-Fluoro-2,2-dimethyl-chroman-4-one

1-(4-Fluoro-2-hydroxy-phenyl)-ethanone (5.0 g, 32.44 mmol), acetone(11.92 mL, 162.2 mmol) and pyrrolidine (2.7 mL, 32.44 mmol) weredissolved in 20 mL benzene, and the reaction mixture was refluxed forfour hours. The reaction mixture was cooled to room temperature andpartitioned between ethyl acetate and 1 N HCl. The organic layer wasdried over MgSO₄, and solvent was evaporated under reduced pressure. Theresulting residue was chromatographed (15% ethyl acetate in hexaneseluting through silica) and solvent was removed to yield 3.33 g (17.16mg, 53%) of 7-fluoro-2,2-dimethyl-chroman-4-one as an oil. MS: 195(M+H)⁺.

Step 2

7-Benzenesulfanyl-2,2-dimethyl-chroman-4-one

The procedure of step 3 of preparation 1 was used to provide 1.49 g of7-Benzenesulfanyl-2,2-dimethyl-chroman-4-one. MS: 285 (M+H)⁺.

Step 3

7-Benzenesulfonyl-2,2-dimethyl-chroman-4-one

The procedure of step 4 of preparation 1 was used to provide 1.10 g of7-Benzenesulfonyl-2,2-dimethyl-chroman-4-one. MS: 317 (M+H)⁺.

Using the procedure of Preparation 2 but replacing benzenethiol in step3 with 3-fluorobenzenethiol,7-(3-fluoro-benzenesulfonyl)-2,2-dimethyl-chroman-4-one was prepared.

Example 1 1-(7-Benzenesulfonyl-chroman-4-yl)-piperazine

The synthetic procedure described in this Example was carried outaccording to the process shown in Scheme D.

Step 1

7-Benzenesulfonyl-chroman-4-ol

7-Benzenesulfonyl-chroman-4-one (500 mg, 1.73 mmol) was dissolved in 15mL MeOH, and sodium borohidride (72 mg, 1.9 mmol) was added. Thereaction mixture was stirred at room temperature for one hour, and wasthen partitioned between water and ethyl acetate. The combined organiclayers were dried over MgSO₄, and solvent was removed under reducedpressure to give 483 mg of crude 7-benzenesulfonyl-chroman-4-ol. MS: 291(M+H)⁺.

Step 2

7-Benzenesulfonyl-4-chloro-chroman

7-Benzenesulfonyl-chroman-4-ol (483 mg, 1.66 mmol) was dissoved in 10 mLtoluene, and 182 uL (02.49 mmol) of thionyl chloride was added. Thereaction was refluxed for two hours, and then cooled to roomtemperature. Solvent was removed under reduced pressure to yield7-benzenesulfonyl-4-chloro-chroman (512 mg) as a crude oil. MS: 308(M+H)⁺.

Step 3

4-(7-Benzenesulfonyl-chroman-4-yl)-piperazine-1-carboxylic acidtert-butyl ester

7-Benzenesulfonyl-4-chloro-chroman (512 mg, 1.65 mmol), Boc-piperazine(piperazine-1-carboxylic acid tert-butyl ester, 371 mg, 1.92 mmol),sodium iodide (50 mg) and potassium carbonate (275 mg) were added to 5mL of DMF, and the reaction mixture was heated to 70° C. overnight. Thereaction mixture was cooled and partitioned between ethyl acetate andwater, and the combined organic layers were dried over MgSO₄. Solventwas removed under reduced pressure, and the residue was chromatographed(silica gel, using 30% ethyl acetate in hexanes) to yield 400 mg of4-(7-Benzenesulfonyl-chroman-4-yl)-piperazine-1-carboxylic acidtert-butyl ester.

Step 4

1-(7-Benzenesulfonyl-chroman-4-yl)-piperazine

[4-(7-Benzenesulfonyl-chroman-4-yl)-piperazine-1-carboxylic acidtert-butyl ester (400 mg) was dissolved in 5 mL of 2N HCl/EtOH. Thereaction mixture was refluxed for one hour, cooled to room temperature,and Et₂O was added. 1-(7-Benzenesulfonyl-chroman-4-yl)-piperazinehydrochloride (152 mg) was collected by filtration. Mp: 243.0-249.0° C.MS: 357 (M+H)⁺.

Additional compounds prepared by the procedure of Example 1, using7-benzenesulfonyl-dimethyl-chroman-4-one or7-benzenesulfonyl-2,2-dimethyl-chroman-4-one with the appropriateamines, are shown in Table 1.

Example 2(7-Benzenesulfonyl-chroman-4-yl)-(2-piperidin-1-yl-ethyl)-amine

The synthetic procedure described in this Example was carried outaccording to the process shown in Scheme E.

7-Benzenesulfonyl-chroman-4-one (100 mg, 0.347 mmol) and2-piperidin-1-yl-ethylamine (45 mg, 0.347 mg) were dissolved in 5 mL ofmethylene chloride, and the reaction mixture was refluxed for two hours.The reaction mixture was cooled to room temperature, and 110 mg (0.52mmol) of NaBH(OAc)₃ was added. The reaction mixture was refluxed for 1hour, cooled to room temperature, and partitioned between water andethyl acetate.l The combined organic layers were dried over MgSO4, andsolvent was removed under reduced pressure to yield 60 mg of7-benzenesulfonyl-chroman-4-yl)-(2-piperidin-1-yl-ethyl)-amine MS: 402(M+H)⁺. This crude product was dissolved in 2 mL of 2N HCl/EtOH, andrecrystallized by addition of Et₂O to provide 40 mg of7-benzenesulfonyl-chroman-4-yl)-(2-piperidin-1-yl-ethyl)-aminehydrochloride. Mp: 151.4-153.2° C.

Using 7-benzenesulfonyl-dimethyl-chroman-4-one or7-benzenesulfonyl-2,2-dimethyl-chroman-4-one with the appropriateamines, were prepared and are shown in Table 1.

Example 3

Formulations

Pharmaceutical preparations for delivery by various routes areformulated as shown in the following Tables. “Active ingredient” or“Active compound” as used in the Tables means one or more of theCompounds of Formula I. Composition for Oral Administration Ingredient %wt./wt. Active ingredient 20.0% Lactose 79.5% Magnesium stearate  0.5%

The ingredients are mixed and dispensed into capsules containing about100 mg each; one capsule would approximate a total daily dosage.Composition for Oral Administration Ingredient % wt./wt. Activeingredient 20.0%  Magnesium stearate 0.5% Crosscarmellose sodium 2.0%Lactose 76.5%  PVP (polyvinylpyrrolidine) 1.0%

The ingredients are combined and granulated using a solvent such asmethanol. The formulation is then dried and formed into tablets(containing about 20 mg of active compound) with an appropriate tabletmachine. Composition for Oral Administration Ingredient Amount Activecompound 1.0 g Fumaric acid 0.5 g Sodium chloride 2.0 g Methyl paraben0.15 g Propyl paraben 0.05 g Granulated sugar 25.5 g Sorbitol (70%solution) 12.85 g Veegum K (Vanderbilt Co.) 1.0 g Flavoring 0.035 mlColorings 0.5 mg Distilled water q.s. to 100 ml

The ingredients are mixed to form a suspension for oral administration.Parenteral Formulation Ingredient % wt./wt. Active ingredient 0.25 gSodium Chloride qs to make isotonic Water for injection 100 ml

The active ingredient is dissolved in a portion of the water forinjection. A sufficient quantity of sodium chloride is then added withstirring to make the solution isotonic. The solution is made up toweight with the remainder of the water for injection, filtered through a0.2 micron membrane filter and packaged under sterile conditions.Suppository Formulation Ingredient % wt./wt. Active ingredient  1.0%Polyethylene glycol 1000 74.5% Polyethylene glycol 4000 24.5%

The ingredients are melted together and mixed on a steam bath, andpoured into molds containing 2.5 g total weight. Topical FormulationIngredients grams Active compound 0.2-2 Span 60 2 Tween 60 2 Mineral oil5 Petrolatum 10 Methyl paraben 0.15 Propyl paraben 0.05 BHA (butylatedhydroxy anisole) 0.01 Water q.s. 100

All of the ingredients, except water, are combined and heated to about60° C. with stirring. A sufficient quantity of water at about 60° C. isthen added with vigorous stirring to emulsify the ingredients, and waterthen added q.s. about 100 g.

Nasal Spray Formulations

Several aqueous suspensions containing from about 0.025-0.5 percentactive compound are prepared as nasal spray formulations. Theformulations optionally contain inactive ingredients such as, forexample, microcrystalline cellulose, sodium carboxymethylcellulose,dextrose, and the like. Hydrochloric acid may be added to adjust pH. Thenasal spray formulations may be delivered via a nasal spray metered pumptypically delivering about 50-100 microliters of formulation peractuation. A typical dosing schedule is 2-4 sprays every 4-12 hours.

Example 4

Radioligand Binding Studies

This example illustrates in vitro radioligand binding studies ofcompound of formula I.

The binding activity of compounds of this invention in vitro wasdetermined as follows. Duplicate determinations of 5-HT₆ ligand affinitywere made by competing for binding of [³H]LSD in cell membranes derivedfrom HEK293 cells stably expressing recombinant human 5-HT₆ receptor.Duplicate determinations of 5-HT₂A ligand affinity were made bycompeting for binding of [³H]Ketanserin(3-(2-(4-(4-fluorobenzoyl)piperidinol)ethyl)-2,4(1H,3H)-quinazolinedione)in cell membranes derived from CHO-K1 cells stably expressingrecombinant human 5-HT_(2A) receptor. Membranes were prepared from HEK293 cell lines by the method described by Monsma et al., MolecularPharmacology, Vol. 43 pp. 320-327 (1993), and from CHO-K1 cell lines asdescribed by Bonhaus et al., Br J Pharmacol. June; 115(4):622-8 (1995).

For estimation of affinity at the 5-HT₆ receptor, all determinationswere made in assay buffer containing 50 mM Tris-HCl, 10 mM MgSO₄, 0.5 mMEDTA, 1 mM ascorbic acid, pH 7.4 at 37° C., in a 250 microliter reactionvolume. For estimation of affinity at the 5-HT_(2A) receptor alldeterminations were made in assay buffer containing 50 mM Tris-HCl, 5 mMascorbic acid, 4 mM CaCl₂, pH 7.4 at 32° C., in a 250 microliterreaction volume.

Assay tubes containing [³H] LSD or [³H]Ketanserin (5 nM), competingligand, and membrane were incubated in a shaking water bath for 75 min.at 37° C. (for 5-HT₆) or 60 min. at 32° C. (for 5-HT_(2A)), filteredonto Packard GF-B plates (pre-soaked with 0.3% PEI) using a Packard 96well cell harvester and washed 3 times in ice cold 50 mM Tris-HCl. Bound[³H] LSD or [³H]Ketanserin were determined as radioactive counts perminute using Packard TopCount.

Displacement of [³H]LSD or [³H]Ketanserin from the binding sites wasquantified by fitting concentration-binding data to a 4-parameterlogistic equation:${binding} = {{basal} + \left( \frac{{B\quad\max} - {basal}}{1 + 10^{{- {Hill}}\quad{({{\log\quad\lbrack{ligand}\rbrack} - {\log\quad{IC}_{50}}}}}} \right)}$where Hill is the Hill slope, [ligand] is the concentration of competingradioligand and IC₅₀ is the concentration of radioligand producinghalf-maximal specific binding of radioligand. The specific bindingwindow is the difference between the Bmax and the basal parameters.

Using the procedures of this Example, compounds of Formula I were testedand found to be selective 5-HT₆ antagonists, selective 5-HT₂Aantagonists, or both. For example, the compound1-(7-benzenesulfonyl-chroman-4-yl)-piperazine exhibted a pKi ofapproximately 9.38 for 5-HT₆, and a pKi of approximately 7.33 for5-HT_(2A).

Example 5

Cognition Enhancement

The cognition-enhancing properties of compounds of the invention may bein a model of animal cognition: the object recognition task model.4-month-old male Wistar rats (Charles River, The Netherlands) were used.Compounds were prepared daily and dissolved in physiological saline andtested at three doses. Administration was always given i.p. (injectionvolume 1 ml/kg) 60 minutes before Ti. Scopolamine hydrobromide wasinjected 30 minutes after compound injection. Two equal testing groupswere made of 24 rats and were tested by two experimenters. The testingorder of doses was determined randomly. The experiments were performedusing a double blind protocol. All rats were treated once with each dosecondition. The object recognition test was performed as described byEnnaceur, A., Delacour, J., 1988, A new one-trial test forneurobiological studies of memory in rats. 1: Behavioral data. Behav.Brain Res. 31, 47-59.

While the present invention has been described with reference to thespecific embodiments thereof, it should be understood by those skilledin the art that various changes may be made and equivalents may besubstituted without departing from the true spirit and scope of theinvention. In addition, many modifications may be made to adapt aparticular situation, material, composition of matter, process, processstep or steps, to the objective spirit and scope of the presentinvention. All such modifications are intended to be within the scope ofthe claims appended hereto.

1. A compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein: m is from 0 to3; p is from 1 to 3; q is 0, 1 or 2; Ar is optionally substituted arylor optionally substituted heteroaryl; each R¹ is independently halo,alkyl, haloalkyl, heteroalkyl, cyano, —S(O)_(t)—R^(a),—C(═O)—NR^(b)R^(c), —SO₂—NR^(b)R^(c), —N(R^(d))—C(═O)—R^(e),—C(═O)N(R^(d))—, or —C(═O)—R^(e), where t is from 0 to 2, R^(a), R^(b),R^(c), R^(d) and R^(e) each independently is hydrogen or alkyl, andR^(f) is hydrogen, alkyl, alkoxy or hydroxy;

R⁷ is X is —O— or —NR⁹—; n is 2 or 3; R³, R⁴, R⁵ and R⁶ eachindependently is hydrogen or alkyl; R⁷ and R⁸ each independently ishydrogen or alkyl, or R⁷ and R⁸ together with the nitrogen to which theyare attached may form a four-to-six-membered ring that optionallyincludes an additional heteroatom selected from O, N and S, or one of R⁷and R⁸ and one of R⁵ and R⁶ together with the atoms to which they areattached may form a four-to-six-membered ring that optionally includesan additional heteroatom selected from O, N and S; and R⁹ is hydrogen oralkyl, or when R⁷ is hydrogen or methyl, R⁹ together with R⁸ and theatoms to which they are attached may form a six-membered ring.
 2. Thecompound of claim 1, wherein p is
 2. 3. The compound of claim 2, whereinq is
 2. 4. The compound of claim 3, wherein Ar is optionally substitutedphenyl.
 5. The compound of claim 4, wherein m is 0 or
 1. 6. The compoundof claim 5, wherein X is —NR⁹—.
 7. The compound of claim 5, wherein R³and R⁴ are hydrogen.
 8. The compound of claim 6, wherein n is
 2. 9. Thecompound of claim 8, wherein R⁵ and R⁶ are hydrogen.
 10. The compound ofclaim 9, wherein R⁷ and R⁸ are hydrogen.
 11. The compound of claim 9,wherein one of R⁷ and R⁸ is hydrogen and the other is alkyl.
 12. Thecompound of claim 9, wherein R⁷ and R⁸ are alkyl.
 13. The compound ofclaim 9, wherein R⁷ and R⁸ together with the nitrogen to which they areattached form six-membered ring.
 14. The compound of claim 9, wherein R⁹is hydrogen.
 15. The compound of claim 9, wherein R⁷ is hydrogen ormethyl and R⁸ and R⁹ together with the atoms to which they are attachedform a six-membered ring.
 16. The compound of claim 6, wherein n is 3.17. The compound of claim 16, wherein R⁵ and R⁶ are hydrogen.
 18. Thecompound of claim 17, wherein R⁷ and R⁸ are hydrogen.
 19. The compoundof claim 17, wherein one of R⁷ and R⁸ is hydrogen and the other isalkyl.
 20. The compound of claim 17, wherein R⁷ and R⁸ are alkyl. 21.The compound of claim 17, wherein R⁷ and R⁸ together with the nitrogento which they are attached form six-membered ring.
 22. The compound ofclaim 17, wherein R⁹ is hydrogen.
 23. The compound of claim 1, whereinsaid compound is of the formula II:

and wherein m, q, Ar, R¹, R², R³ and R⁴ are as recited in claim
 1. 24.The compound of claim 1, wherein said compound is of the formula III:

wherein: s is from 0 to 4; each R¹⁰ is independently halo, alkyl,haloalkyl, heteroalkyl, cyano, —S(O)_(t)—R^(a), —C(═O)—NR^(b)R^(c),—SO₂—NR^(b)R^(c), —N(R^(d))—C(═O)—R^(e), —C(═O)N(R^(d))—, or—C(═O)—R^(e), where t is from 0 to 2, R^(a), R^(b), R^(c), R^(d) andR^(e) each independently is hydrogen or alkyl, and R^(f) is hydrogen,alkyl, alkoxy or hydroxy; and X, R⁷ and R⁸ and are as recited inclaim
 1. 25. The compound of claim 1, wherein said compound is of theformula IV:

wherein: s is from 0 to 4; each R¹⁰ is independently halo, alkyl,haloalkyl, heteroalkyl, cyano, —S(O)_(t)—R^(a), —C(═O)—NR^(b)R^(c),—SO₂—NR^(b)R^(c), —N(R^(d))—C(═O)—R^(e), —C(═O)N(R^(d))—, or—C(═O)—R^(e), where t is from 0 to 2, R^(a), R^(b), R^(c), R^(d) andR^(e) each independently is hydrogen or alkyl, and R^(f) is hydrogen,alkyl, alkoxy or hydroxy; and R⁷ is hydrogen or methyl.
 26. Apharmaceutical composition comprising an effective amount of thecompound of claim 1 in admixture with a pharmaceutically acceptablecarrier.
 27. A method for treating a central nervous system diseasestate selected from psychoses, schizophrenia, manic depressions,neurological disorders, memory disorders, attention deficit disorder,Parkinson's disease, amyotrophic lateral sclerosis, Alzheimer's disease,food uptake disorders, and Huntington's disease, said method comprisingadministering to said subject a therapeutically effective amount of acompound of claim 1.